As an opioid receptor, three opioid receptors, μ-, κ- and δ-opioid receptors have been known (K. K. Mikusu, Opioid no Subete, 25-36 (1999)). The μ-opioid receptor is distributed in the cerebral cortex, amygdaloid nucleus and the like, and main agonists are morphine, codeine and the like. The κ-opioid receptor is distributed in the hypothalamus, spinal cord and the like, and its agonists are ketocyclazocine and the like. The δ-opioid receptor is distributed in the extrapyramidal system, and its agonists are enkephalin and the like. The μ-opioid receptor agonist typified by morphine and codeine has an excellent analgesic activity, but its dependence on the body and mind is strong, and it involves side effects such as complication of constipation.
Meanwhile, the κ-opioid receptor agonist is characterized in that it does not exhibit dependence unlike morphine, and trans-2-(3,4-dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]acetamide (U-50488), 2,2-diphenyl-N-[2-(3-(S)-hydroxy-1-pyrrolidinyl)-1-(S)-phenylethyl]Methylacetamide (Asimadoline) and the like are known (K. K. Mikusu, “Opioid no Subete”, 25-36 (1999), K. K. Mikusu, “Opioid no Subete”, 213-232 (1999)).
Pain is roughly classified into acute pain and chronic pain. The acute pain is pain accompanied by tissue disorders, and causal association with tissue disorders is clear. Meanwhile, the chronic pain is pain which continues even after curing tissue disorders, and no clear organic cause has been found out. However, it has been reported that a plastic change of a descending inhibition system participates in development of the chronic pain (K. K. Mikusu, “Opioid Chiryo”, 246-253 (2000)). When pain is prolonged, a pain threshold is gradually decreased, and pain is felt also due to an action, a tactile sense or the like which has not given a feel of pain. The pain threshold here referred to indicates a sensitivity of pain. More specifically, it indicates the minimum level of stimulation which gives a feel of pain.
Accordingly, the decrease in pain threshold increases the sensitivity of pain, and amplifies the same. Therefore, when the decrease in pain threshold can be inhibited, it is possible to effectively treat the chronic pain. Japan J. Pharmacol., 57, 243-250 (1991) reports that neurotropin, an agent for treating chronic pain can inhibit a decrease in pain threshold by activating a descending inhibition system. However, its chronic pain-inhibiting effect is not necessarily satisfactory.